Asthma control and its predictors in Ethiopia: Systematic review and meta-analysis

Background Determining the status of asthma control and identifying risk factors for poor asthma control is a key strategy for curbing the negative health impacts and the financial burden of the disease. Therefore, this review was aimed to determine the rate of asthma control and assess the predictors of uncontrolled asthma in Ethiopia. Methods PubMed, Web of Science, and Google Scholar searches were performed using key terms; “asthma, bronchial asthma, control, controlled, uncontrolled and Ethiopia” up to October 16, 2020. University repositories were also searched to retrieve gray literature. The results were presented as a prevalence rate with a 95% confidence interval (CI). Subgroup analysis and meta-regression were performed to identify the sources of heterogeneity in the outcomes. Results From 1,388 patients, based on the Global Initiative for Asthma (GINA) symptom control, the rate of the uncontrolled asthma was 45.0% (95% CI 34.0% - 56.0%) with a considerable heterogeneity between the studies; (I2: 94.55, p< 0.001). About 19.0% (95% CI 10.0% - 29.0%); (I2: 96.04, p< 0.001) of the asthma patients had a well-controlled asthma. Moreover, 36.0% (95% CI 22.0% - 50.0%), (I2: 97.11, p< 0.001) of patients had a partly controlled asthma. Similarly, based on the asthma control test (ACT), the rate of well-controlled asthma was 22.0% (95% CI 3% - 42.0%), with considerable heterogeneity between the studies; (I2: 97.75, p< 0.001). The most frequent predictors of uncontrolled asthma were incorrect inhalation techniques, frequent SABA use, moderate/severe persistent asthma, history of exacerbations, presence of comorbidities, use of oral corticosteroids, and irregular follow-up. Conclusion The rate of uncontrolled asthma in Ethiopia was high. Several factors are associated with uncontrolled asthma. Comprehensive asthma educations at each follow-up visit should be strengthened to minimize the morbidity and the cost of uncontrolled asthma.

evidence for the national prevalence of uncontrolled asthma and its predictors in Ethiopia. The finding of this study would have a valuable contribution for clinicians and policy makers to design appropriate strategy to tackle the problems associated with poor asthma control, which ultimately affects the quality of asthma care.

Objective
This study aimed to estimate the rate of asthma control and the predictors of uncontrolled asthma among adult asthmatic patients in Ethiopia.

Methods
This systematic review and meta-analysis was reported by Preferred Reporting Items for Systematic reviews and Meta-analysis (PRISMA) statement guideline for systematic reviews and meta-analysis and guided by PRISMA checklists [16]. This review did not have a protocol and hence not registered.

Data sources and searching strategies
Two investigators (TM and TA) independently searched electronic databases; PubMed, Web of Science, and Google Scholar. Other sources such as Jimma and Addis Ababa University's digital catalogs were also explored to retrieve unpublished documents. Electronic databases were searched using the combinations of the following key terms and Mesh terms along with the Boolean operators ("OR, AND"): "Asthma, bronchial asthma, control, controlled, uncontrolled, Ethiopia". The searching was conducted from inception to October 16, 2020. The PubMed search detail was as follows: ((Asthma [Mesh] OR Asthma [tw] OR "bronchial asthma" [ [tw]). Manual searches were also performed to find the reference lists of the selected articles. The PubMed search detail found at S3 Table in S1 Annex.

Inclusion and exclusion criteria
All available articles reporting asthma control were included. Articles reporting patients with cardiac asthma were excluded. There were no articles that reported asthma control status in pediatric patients.

Data extraction
A protocol for data extraction was designed by the authors and data were extracted independently by two authors (TM and TA). Any disagreements were resolved by consensus through discussion and by the authors (GZ and GT). Data were extracted on the name of the first author and year of publication, place of study, study design, participants' sociodemographic, sample size, medication prescribed, asthma control status, and predictors of uncontrolled asthma.

Outcomes definitions
The primary outcome of this systematic review and meta-analysis is rate of asthma control. It was reported either as per the Global Initiative for Asthma (GINA) control definition or Asthma control test (ACT) questionnaire. The secondary outcome was to determine the predictors for uncontrolled asthma.
As per the GINA guideline and other literatures [6,14], asthma symptom control was classified as well controlled, partly controlled, and uncontrolled/poorly controlled. Well-controlled asthma was defined by the absence of daytime symptoms (no more than twice a week), the absence of nighttime symptoms, no limitations in activities, and limited need for rescue medication (not more than twice a week), and no exacerbations. Partially controlled asthma was present when daytime symptoms or rescue medication use was present more than twice per week and night waking or activity limitation was present in any week and exacerbations are present one or more per year. Uncontrolled asthma was defined as the presence of any three or more of these individual features within any week. According to the standardized selfadministered ACT [6,17], asthma control was classified as not well-controlled and well-controlled. Patients were classified as not well-controlled when the overall ACT score is less than or 19 and well-controlled when the overall ACT score is above 20.

Assessment of quality of the studies
Two authors (GZN and GTD) independently appraised the quality of the included studies using the AXIS tool for Cross-sectional Studies [18] and Modified Newcastle Ottawa scale [19] for a prospective observational and case-control study. In the AXIS tool, for every correct answer, "yes" was assigned to each of the twenty questions. Otherwise, it was assigned "no" and not applicable (NA). The details of the quality appraisal results were found in S1 Table in S1 Annex.

Data analysis and synthesis
We conducted a meta-analysis using OpenMetaAnalyst. Forest plots were used to estimate pooled prevalence with a 95% confidence interval (CI) to provide a visual summary of the data. To evaluate heterogeneity among studies, the Cochran's Q test and I square (I 2 ) indices were used. A significance threshold of p < 0.05 was applied to the heterogeneity (I 2 ). At present heterogeneity, a random-effects model was used to compute the overall effect. A subgroup analysis was conducted to detect the impact of geographical regions on the status of asthma control. Meta-regression was also performed to assess the sources of the heterogeneity between the studies. We indexed a separate national prevalence of asthma and COPD to support the evidence (S1 and S2 Figs in S1 Annex).

Study selection
The details of our search strategy were depicted in Fig 1. From all database searches, 2,582 records were identified. Twenty-three duplicates were removed keeping 2,559 records. Moreover, 2,397 records were removed because the titles and abstracts are unrelated to the outcomes of the review. The remaining 162 full articles were critically assessed for eligibility. Then, 151 articles were removed due to no reported outcomes of interest or asthma control. Finally, 11 full articles were selected and included in qualitative and quantitative analysis (Fig 1).
Two studies [15,24] were reported the asthma control as well-controlled and poorly controlled based on the GINA symptom control. In a study by Zewudie et al [15], 50% of the asthma patients were assessed to have poorly controlled asthma, while, in a study by Dalo et al [24], 56.2% of the asthma patients were assessed to have a poorly controlled asthma.

Asthma control based on the Asthma Control Test (ACT)
The ACT tool was used in three studies [17,21,25] for assessing asthma control. ACT score � 20 out of 25 total scores was used as a cut-point for well-controlled asthma. Among 697 asthma patients assessed, 22% (95% CI 3% -42%) of the patients had well-controlled asthma. Considerable heterogeneity was detected among the studies (I 2 = 97.75%, p<0.001) (Fig 6). The remaining 78% (95% CI 58-97%) of the patients had uncontrolled asthma (Fig 7).

Risk of bias
Studies were critically appraised using the AXIS tool (S1 Table in S1 Annex). Almost similar issues were identified in the domains of the appraisal tool. In many studies, the authors did not address the issue of non-responders, provide information, or categorize. In some of the studies, the selection of the participants was not representative of the source populations because convenience sampling was used, and it was not addressed how representative these samples were to the true population. In one study [22], the sample size for the participants was not justified. In a study by Dalo et al [24], since the design was retrospective, the issues of the nonrespondents were described as "not applicable". Two studies [15,27] were critically appraised using the Modified Newcastle-Ottawa Quality Assessment Scale (S2 Table in S1 Annex). The quality of the two studies was moderate [15] and high quality [27].

Discussion
The global epidemiological transitions are responsible for the changing burden of asthma in low and middle-income countries [28,29]. In Ethiopia, the current national prevalence of asthma is 8.7% (95% CI 7.4-10.1%) (S1 Fig in S1 Annex). Although this figure is lower than the current national prevalence of COPD (18.3%) (S2 Fig in S1 Annex), it is causing a blistering attack on the health care system due to its substantial morbidity, mortality and higher health care costs [1,[30][31][32]. The key strategy for curbing such public health sufferings relies on proper asthma control and the identification of population-specific risk factors for uncontrolled asthma. Hence, this meta-analysis and systematic review summarized the rate of asthma control and predictors of uncontrolled asthma in Ethiopia.  This systematic review found 45.0% of uncontrolled asthma and 36.0% of partly controlled asthma in Ethiopia. Incorrect inhalation techniques, frequent SABA use, moderate/severe persistent asthma, history of exacerbations, presence of comorbidities, use of oral corticosteroids, and irregular follow-up were associated with uncontrolled asthma. In major cities; Jimma and Addis Ababa, the rate of uncontrolled asthma was 44.0% and 45.0%, respectively. Moreover, the study found much worrisome figure for the rate of well-controlled asthma. It was 19.0% at the national level, 14.0%, and 25.0%, respectively, in Jimma and Addis Ababa.
Despite the advances achieved in the development of new diagnostic tests like the fractional exhaled nitric oxide (FeNO), new treatments like monoclonal antibodies, and the wide availability of management guidelines, asthma control remained the major clinical challenge [33]. Added to the increased prevalence of asthma in adults (8.7%; S1 Fig in S1 Annex) in Ethiopia, the burden of uncontrolled asthma could be more throbbing to the already crippling health system.
This meta-analysis revealed based on the GINA asthma symptom control, 45.0%, 36%, and 19.0% of the asthma patients had uncontrolled, partially controlled, and controlled asthma in Ethiopia, respectively. Comparable findings were reported from a study done in European countries, where the rate of uncontrolled, partially controlled and controlled asthma was 45.0%, 34.8%, and 20.0% among adults, respectively [34]. In 2016, the Centers for Disease Control and Prevention (CDC) reported more than 60% of American adults with asthma had uncontrolled asthma [35]. Similarly, compared to the finding of this meta-analysis, a higher rate of uncontrolled asthma was reported in studies from France 48% [36], North Africa 50.9% [37], and Uganda 67.0% [38]. However, lower findings were reported from Brazil 34.2% [39], Morocco 29% [13], Japan 15.1% [40], Latin America (36.0%) [41], Saudi Arabia 38.0% [42], Sweden 39.6% [43], Middle East and North Africa 41.5% [44] and Asia-Pacific countries 30.0% [45]. These differences could be due to the geographical location, seasonal difference, number of the participants included, and the asthma service delivery at the institutions.
This meta-analysis also revealed a significant proportion of uncontrolled asthma in two major cities of Ethiopia, Jimma and Addis Ababa. It is obvious that these settings are responsible to manage a majority of the refractory cases. The increased proportion of uncontrolled asthma in these places was partly due to the presence of larger hospitals reserved for referral services in these regions. A body of evidence also showed geographical locations and urbanization paly a decisive role in determining the prevalence of asthma and its sensitivity to therapy [46,47].
Based on the asthma control test (ACT), our review showed a higher rate of uncontrolled asthma in Ethiopia (78.0%). Similarly, a comparable finding was reported by Benkheder et al from North Africa [37] and Laforest et al from French [48], where 71.3% and 71.0% of the patients had uncontrolled asthma, respectively. However, in studies by Corrado et al from Italy [49], Zhong et al from China [50], Kabengele et al from Congo [51], and Stanford from the USA [52], relatively lower (51.3%, 55.1%, 56.0%, and 58%) of asthma patients had uncontrolled asthma, respectively. In Nigeria, a study reported 82.9% of the patients had uncontrolled asthma, even though the sample size of the study was small [53].
Several factors may contribute to poor disease control, with significant variability between different countries [54,55]. Identifying these factors is fundamental for improving asthma outcomes. This systematic review revealed the most frequently reported predictors for uncontrolled asthma in Ethiopia were incorrect inhalation techniques, frequent SABA use, moderate/severe asthma, comorbid diseases, a history of asthma exacerbations and irregular follow-up.
Similarly, several studies have identified several factors associated with uncontrolled asthma. In studies by AL-Jahdali et al from Saudi Arabia [56], Bharti Chogtu et al from India [57], Fusun Yildiz et al from Turkey [58] and Umoh et al from Nigeria [53], improper use of asthma inhaler devices was associated with poorly controlled asthma. Studies from Sweden [59], Asia-Pacific countries [45] and Germany [60] revealed the overuse of short-acting beta-2 agonists (SABA) was associated with asthma exacerbations and asthma control. Price et al reported more than 40% of asthma patients used their reliever medications three or more times in the previous week, which the author may judge the reason for the high levels of uncontrolled asthma [34]. Several studies also reported patients with severe asthma [12,[61][62][63], history of asthma exacerbations/hospitalizations [45,49,53,61,63,64], who had comorbid diseases [13,[50][51][52]65], smoking [43,52,66], oral corticosteroid use [12,63], and irregular follow-up visit [56,67] were more likely had a higher rate of uncontrolled asthma.
Given the lack of previous attempts in producing such kind of aggregated data, the finding could hint at the adequacy of the health care service in dealing with the problem. It also provides valuable information for clinicians to design appropriate strategies that can help to provide proper care for asthmatic patients. The finding is also crucial for pharmacy professionals to deal with issues arising from improper use of asthma medication. Moreover, this finding could instigate researchers to further unlock matters related to such a huge burden of uncontrolled asthma in the current setting.
The major limitation of this review is the measurement of asthma control using GINA symptom control than lung function tests. This may overestimate the status of asthma control in the current settings. Heterogeneity, lack of uniformity for measuring asthma control, the inclusion of poor-quality study design, failure to identify specific groups with uncontrolled asthma, the inclusion of studies limited to a few geographic locations are some of the other shortcomings of this review.

Conclusion
The rate of uncontrolled asthma in Ethiopia is much concerning. The most frequently reported predictors for uncontrolled asthma were; incorrect inhalation techniques, frequent SABA use, moderate/severe asthma, comorbid diseases, a history of asthma exacerbations and irregular follow-up visit. Revising the asthma management approaches and asthma educations at each follow-up visit should be strengthened to minimize the morbidity of uncontrolled asthma. Moreover, further research with a high-quality design is required to disclose the category of patients with a high proportion of uncontrolled asthma.